) Ovarian carcinoma (OC) is the fourth most frequent form of cancer death of women in the United States. Approximately 1 in 70 women in the US will develop OC; in advanced stages of the disease there is a 5-year survival of about 15-20%. Present methods of treatment for advanced stage OC are not effective and the recurrence rate in patients with advanced stage disease is high. Pivitol Biosciences has shown that the peptide contortrostatin (CN) inhibited growth and dissemination of human ovarian cancer (OVCAR-5 cells) in an animal model. Using the chick embryo chorioallantoic membrane (CAM) model system, CN blocked tumor cell dissemination and inhibited angiogenesis induced by OVCAR-5 cells. Thus, CN has a two pronged attack on ovarian cancer, it blocks implantation and blood flow to the tumors to prevent metastasis. Our pre-clinical investigations on the anti-cancer activities of CN indicate that this compound is a promising new therapy for OC. As a next step in the pre-clinical development of CN, in this proposal, we will determine the optimal formulations of CN to treat OC. Since OC disseminates inside the peritoneal cavity, local delivery of CN by intraperitoneal (i.p.) injection is a feasible approach for administering this anticancer agent. We have already shown that i.p. administration of CN can inhibit progression of OVCAR-5 in vivo in animals. In this proposal we will test whether conjugating CN with colloidal gold or developing a sustained release formulation of CN using a liposome delivery system provides optimal anti-cancer activity for CN. We will test whether these formulations maintain their anti-angiogenic effectiveness in treating OC. This proposal will establish the foundation for future studies (phase II application) to complete the pre-clinical development of CN so that an IND can be filed to test CN in human cancer patients.
Antiangiogenic therapy offers significant promise for the treatment of cancer. However, no antiangiogenic agent has yet been approved for clinical use. Theoretically, this form of anticancer therapy has many advantages: it is not cytotoxic and should not be limited by acquired drug resistance. The agent we are investigating, contortrostatin, is unique in that it inhibits both tumor cell progression as well as angiogenesis. The ability to target contortrostatin to the tumor site will significantly enhance its translational potential. Although this proposal targets ovarian cancer, this form of therapy should be widely applicable for many forms of cancer. The potential market for cancer antiangiogenic therapy could approach $3 billion by 2005.
| Golubkov, Vladislav; Garcia, Agustin; Markland, Francis S (2005) Action of fenretinide (4-HPR) on ovarian cancer and endothelial cells. Anticancer Res 25:249-53 |
| Swenson, Stephen; Costa, Fritz; Minea, Radu et al. (2004) Intravenous liposomal delivery of the snake venom disintegrin contortrostatin limits breast cancer progression. Mol Cancer Ther 3:499-511 |
| Golubkov, Vladislav; Hawes, Debra; Markland, Francis S (2003) Anti-angiogenic activity of contortrostatin, a disintegrin from Agkistrodon contortrix contortrix snake venom. Angiogenesis 6:213-24 |
